Cancer cachexia/anorexia is a common, devastating manifestation of many malignancies and contributes significantly to patient morbidity and mortality. The etiology of cancer cachexia/anorexia is multifactorial and existing treatment strategies are disappointing. Recent work has identified calcitonin/calcitonin-gene relate peptide (CT/CGRP) neurons as the specific neuronal group in the hindbrain that causes anorexia and weight loss due to infection, inflammation and pain - and this same area of the hindbrain, the parabrachial nucleus, is known to be activated in pre-clinical cancer models. The novel genetic mouse models that elucidated the role of CT/CGRP neurons in 'illness' models of weight loss can also be used to definitively test the mechanistic role of these neurons in cancer cachexia/anorexia. Importantly, our proposed studies evaluate mouse cancer models causing gradual, progressive cachexia/anorexia - more similar to clinical situations. The novel genetic mouse models of inducible inhibition of CT/CGRP neurons allow us to investigate treatment strategies for cancer-induced weight loss rather than focusing merely on cachexia prevention. A second genetic strategy will focus on a key Arcuate nucleus neuronal population - NPY/Agrp neurons - and determine whether tumor- related inhibition of these neurons contributes to the mechanism of cancer cachexia/anorexia and whether inducible activation of these neurons can either prevent or treat established cancer cachexia/anorexia. Critically, our studies will also determine the impact of interventions to treat cancer anorexia on lean body mass and survival. Our proposal has the potential to discover novel therapies for treatment of cancer anorexia and thereby potentially improve the quality of life of patients with cancer.